One cause of disability, particularly in elderly people, is muscular atrophy or the loss of muscle mass, also known as sarcopenia. Aging-related muscular atrophy partly reflects impaired protein synthesis and activation of catabolism [Morley, J. E., Baumgartner, R. N., Roubenoff, R., Mayer, J. and Nair, K. S. (2001), “Sarcopenia,” J. Lab. Clin. Med. 137, 231-243]. Critical illness, including advanced cancer, poorly controlled type 1 diabetes, trauma, sepsis, extensive burn injury, major surgery, and muscular dystrophy are also associated with muscular atrophy.
Cancer patients often experience cachexia characterized by a progressive decrease in both adipose tissue and skeletal muscle mass [van Leeuwen, I. M. M., Zonnefeld, C. and Kooijman, S. (2003), “The embedded tumour: host physiology is important for the evaluation of tumour growth,” Br. J. Cancer 89, 2254-2263]. Natural toxins, such as streptozotocin (STZ), radiotherapy, and various chemotherapies, such as cisplatin (CisPt), doxorubicin, mytomycin C and etoposide, also seem to induce reduction in the muscle and adipose tissue mass [Li, L., Seno, M., Yamada, H. and Kojima, I. (2003), “Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to β-cells in streptozotocin-treated mice,” Am. J. Physiol. Endocrinol. Metab. 285, E577-E583; Baracos, V. R. (2001), “Management of muscle wasting in cancer-associated cachexia,” Cancer 92, 1669-1677; Chen, H., Carlson, E. C., Pellet, L., Moritz, J. T. and Epstein, P. N. (2001), “Overexpression of metallothionein in pancreatic β-cells reduces streptozotocin-induced DNA damage and diabetes,” Diabetes 50, 2040-2046]. It is thought that these agents exert their toxic effects via generation of reactive oxygen species or ROS [Powis, G., Mustacich, D. and Coon, A. (2000), “The role of the redox protein thioredoxin in cell growth and cancer,” Free Radical Biol. Med. 29, 312-322].
There are several known factors that prevent loss of muscle and adipose tissue. Insulin-like growth factor-1 (IGF-1) appears to play a key role in preventing muscle atrophy [Barton-Davis, E. R., Shoturma, D. I., Musaro, A., Rosenthal, N. and Sweeney, H. L. (1998), “Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function,” Proc. Natl. Acad. Sci. USA 95, 15603-15607]. However, during aging the muscle becomes unable to express the autocrine form of IGF-1 in response to mechanical overload resulting in reduced skeletal muscle function [Owino, V., Yang, S. Y. and Goldspink, G. (2001), “Age-related loss of skeletal muscle function and the inability to express the autocrine form of insulin-like growth factor-1 (MGF) in response to mechanical overload,” FEBS Lett. 505, 259-263]. In addition, interleukin-6 (IL-6), a cytokine which plays a central role in inflammation, reduces both the level of circulating IGF-1 and the action of IGF-1 on muscle [Barbieri, M., Ferrucci, L., Ragno, E., Corsi, A., Bandinelli, S., Bonafe, M., Olivieri, F., Giovagnetti, S., Franceschi, C., Guralnik, J. M. and Paolisso, G. (2003), “Chronic inflammation and the effect of IGF-1 on muscle strength and power in older persons,” Am. J. Physiol. Endocrinol. Metab. 284, E481-E487; De Benedetti, F., Alonzi, T., Moretta, A., Lazzaro, D., Costa, P., Poli, V., Martini, A., Ciliberto, G. and Fattori, E. (1997), “Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I,” J. Clin. Invest. 99, 643-650]. Insulin and amino acids, particularly leucine, also seem to play a key role in preventing muscle loss by enhancing protein synthesis [O'Connor, P. M., Bush, J. A., Suryawan, A., Nguyen, H. V. and Davis, T. A. (2002), “Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs,” Am. J. Physiol. Endocrinol. Metab. 284, E110-E119; Anthony, J. C., Anthony, T. G., Kimball, S. R. and Jefferson, L. S. (2001), “Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine,” J. Nutr. 131, 856S-860S]. These, along with additional factors such as growth hormone, testosterone, and resistance exercise, increase metabolism as well as muscle growth and muscle strength [Yarasheski, K. E., Zachwieja, J. J., Campbell, J. A. and Bier, D. M. (1995), “Effect of growth hormone and resistance exercise on muscle growth and strength in older men,” Am. J. Physiol. Endocrinol. Metab. 268, E268-E276; Ferrando, A. A., Sheffield-Moore, M., Yeckel, C. W., Gilkison, C., Jiang, J., Achacosa, A., Lieberman, S. A., Tipton, K., Wolfe, R. R. and Urban, R. J. (2002), “Testosterone administration to older men improves muscle function: molecular and physiological mechanisms,” Am. J. Physiol. Endocrinol. Metab. 282, E601-E607].
Unfortunately, for many patients with debilitating diseases, many of the known therapies used to prevent the loss of muscle and adipose tissue are not ideal. IGF-1 and insulin levels may increase the risk of developing cancer and hypoglycemia after prolonged use. Similarly, growth hormone and testosterone have side effects that make them less than ideal. Nutrition-based therapies also do not significantly help maintenance of muscle mass and body weight.
There are several degenerative diseases of the skeletal muscle, including various forms of muscular dystrophy, that may be treated through transplantation of myoblasts and stem cells [Seale, P., Asakura, A., and Rudnicki, M. A. (2001), “The potential of muscle stem cells,” Develop. Cell 1, 333-342]. Cell-based therapy may also be used to repair damaged skeletal muscle. However, as yet these procedures are limited by a short supply of myoblasts and stem cells and other technical difficulties including ensuring sterility of cell preparations. Therefore, promotion of survival of healthy cells and reversal of protein loss seem to be more viable strategies, particularly in combination, to prevent deterioration of healthy tissues in diseased and treated subjects.